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* Tel Aviv University news release
* Purdue Biological Sciences

April 16, 2009

Researchers find lack of key molecule leads to deafness

WEST LAFAYETTE, Ind. -
Deborah Biesemeier, left,
and Donna Fekete

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Researchers have identified tiny molecules that may lead to big breakthroughs in the treatment of hearing loss and deafness.

An international team, including researchers from Tel Aviv University in Israel and Purdue University, found that lack of these molecules causes abnormal development of the inner ear and leads to progressive hearing loss.

Donna Fekete, the Purdue professor of biological sciences involved in the study, said this new information could provide promising leads to treat hearing loss.

"The molecules we identified could be used as a molecular tool delivered directly into the ears of deaf people to induce regeneration of important sensory cells that would improve hearing," she said. "The molecules also could potentially help people with balance disorders related to inner ear function such as Meniere's disease."

The National Institutes of Health National Institute on Deafness and Other Communication Disorders, or NIDCD, reports that 36 million American adults have some degree of hearing loss.

In many cases of non-congenital hearing loss, the cause is degeneration of specialized sensory cells in the inner ear, called hair cells. Hair cells convert sound waves into electrical impulses that can be interpreted by the brain. According to the NIDCD, excessive noise, certain medications, aging and disease can damage or destroy hair cells. Because humans are unable to replace lost hair cells, hearing declines as they are lost.

The international research team identified microRNAs - tiny pieces of the genetic building block ribonucleic acid, or RNA - critical to the survival of hair cells. MicroRNAs regulate genes by selectively preventing certain genes from making proteins.

Karen Avraham, the Tel Aviv University professor who led the study, said this research shows that a loss of certain microRNAs can cause deafness.

"We found that hair cell microRNAs are regulators involved in the normal development and survival of cells in the inner ear and are necessary for proper hearing," said Avraham, who is a professor in the Department of Human Molecular Genetics. "Until very recently, science only knew that mutation in protein-coding genes caused deafness. We went a layer deeper and discovered that the loss of microRNAs leads to deafness as well."

In recent separate studies conducted in Spain and the United Kingdom, mutations in a single microRNA were reported to cause deafness in humans and mice, showing the importance of microRNAs in the inner ear and the link to human hearing loss, Avraham said.

Earlier research had shown microRNAs to be involved in ear development, but this study is the first to remove the microRNAs at the time when hair cells are just beginning to form, Fekete said. A paper detailing the work was published in the April 14 issue of the Proceedings of the National Academy of Sciences.

In addition to Avraham and Fekete, co-authors of the paper include assistant research scientist Takunori Satoh and research assistant Deborah J. Biesemeier from Purdue; Lilach Friedman, Amiel Dror, Eyal Mor, Tamar Tenne, Ginat Toren and Noam Shomron from Tel Aviv University; and Eran Hornstein from The Weizmann Institute of Science in Rehovot, Israel.

The first microRNA was discovered in 1993, and the field has taken off within the last eight years, Fekete said.

"In a sense it is a whole new way of looking at gene regulation that we didn't know much about 10 years ago," she said. "Now people all over the world from different fields are trying to figure out the roles microRNAs play and how they can be used to improve human health."

Fekete and the Purdue team examined several microRNAs in zebrafish to determine what role each played.

"There are hundreds of microRNAs, and the question is which ones are doing what in terms of keeping hair cells alive and developing properly," Fekete said. "In this paper, we identified two microRNAs that, when removed, reduced the number of hair cells developed."

The missing microRNAs also each caused abnormal development of larger organs of the ear. One prevented development of the semicircular canals involved in balance, and the other prevented development of an organ called an ear-stone that is needed to sense movement, Fekete said.

Additional unpublished work by Satoh and Purdue graduate student Haiqiong Li in Fekete's lab expands the list of microRNAs that regulate hair cell numbers to seven, Fekete said.

Her team next plans to investigate other microRNAs thought to be involved in hair cell development and to look into whether overexpression of these molecules could lead to regeneration of these sensory cells from so-called supporting cells. In earlier research, Fekete showed that hair cells and supporting cells have the same biological origin.

"Research has shown that in other animals supporting cells can give rise to hair cells, so the real challenge is to determine why this doesn't happen in mammals," Fekete said. "One thought is that microRNAs might be able to turn off supporting cell genes and make them more susceptible to becoming hair cells, effectively getting them to switch fates."

Fekete said this research is a good example of the importance of studying animal models.

"The genes that regulate hair cell development and differentiation are very similar between zebrafish and humans," Fekete said. "Animal models, even simple ones, can provide incredibly important data that ultimately can impact human health and disease."

The Israel Science Foundation, European Commission, National Organization for Hearing Research, Deafness Research Foundation and National Institutes of Health funded this research.

Writer: Elizabeth K. Gardner, (765) 494-2081, ekgardner@purdue.edu

Source: Donna Fekete, 765-496-3058, dfekete@purdue.edu

Karen Avraham, karena@post.tau.ac.il

Purdue News Service: (765) 494-2096; purduenews@purdue.edu

PHOTO CAPTION:
Purdue research assistant Deborah Biesemeier, at left, and professor of biological sciences Donna Fekete stand in a zebrafish holding facility. Fekete and Biesemeier used zebrafish to identify key molecules involved in hearing loss and deafness as part of an international research team. (Purdue News Service photo/Andrew Hancock)

A publication-quality photo is available at http://news.uns.purdue.edu/images/+2009/zebrafish-research.jpg


ABSTRACT

MicroRNAs are Essential for Development and Function of Inner-ear Hair Cells in Vertebrates

Lilach M. Friedman, Amiel A. Dror, Eyal Mor, Tamar Tenne, Ginat Toren, Takunori Satoh, Deborah J. Biesemeier, Noam Shomron, Donna M. Fekete, Eran hornstein,
and Karen B. Avraham

MicroRNAs (miRNAs) inhibit the translation of target mRNAs and affect, directly or indirectly, the expression of a large portion of the protein-coding genes. This study focuses on miRNAs that are expressed in the mouse cochlea and vestibule, the two inner ear compartments. A conditional knock-out mouse for Dicer1 demonstrated that miRNAs are crucial for postnatal survival of functional hair cells of the inner ear. We identified miRNAs that have a role in the vertebrate developing inner ear by combining miRNA transcriptome analysis, spatial and temporal expression patterns and bioinformatics. Microarrays revealed similar miRNA profiles in newborn-mouse whole cochleae and vestibules, but different temporal and spatial expression patterns of six miRNAs (miR-15a, miR-18a, miR-30b, miR-99a, miR-182, and miR-199a) may reflect their roles. Two of these miRNAs, miR-15a-1 and miR-18a, were also shown to be crucial for zebrafish inner ear development and morphogenesis. To suggest putative target mRNAs whose translation may be inhibited by selected miRNAs, we combined bioinformatics-based predictions and mRNA expression data. Finally, we present indirect evidence that Slc12a2, Cldn12, and Bdnf mRNAs may be targets for miR-15a. Our data support the hypothesis that inner-ear tissue differentiation and maintenance are regulated and controlled by conserved sets of cell-specific miRNAs in both mouse and zebrafish.


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